Naturally occurring as well as synthetic steroidal glucocorticoids (e.g. cortisol, cortisone, prednisolone, dexamethasone) have been widely used for over fifty years for the treatment of acute and chronic inflammatory and immune disorders. In particular, glucocorticoids have been prescribed for the treatment of rheumatoid arthritis, osteoarthritis, rheumatic fever, asthma, allergic rhinitis, systemic lupus erythematosus, chronic obstructive pulmonary disease, Crohn's disease, inflammatory bowel disease, and ulcerative colitis. However, the use of glucocorticoids is often associated with severe and sometimes irreversible side effects such as bone loss/osteoporosis, hyperglycemia, diabetes mellitus, hypertension, glaucoma, muscle atrophy, Cushing's syndrome, and psychosis. Thus, there remains a need for alternative therapies which possess the beneficial effects of steroidal glucocorticoids, but with a reduced likelihood or incidence of attendant side effects.
Glucocorticoids exert their pharmacological effects by regulating gene transcription after the formation of a complex with the glucocorticoid receptor (GR). This GR-glucocorticoid complex affects gene transcription by distinct mechanisms. First, following binding of the glucocorticoid, the complexed GR translocates to the nucleus where it acts as a dimer in binding to DNA glucocorticoid hormone response elements (GREs) in the promoter regions of particular genes. The GR-glucocorticoid/GRE complex then, in turn, activates (transactivation) or inhibits transcription of proximally located genes. Conversely, the GR-glucocorticoid complex may negatively regulate gene transcription by a process that does not involve binding to DNA. In this process, termed transrepression, following binding of the glucocorticoid, the complexed GR enters the nucleus where it acts as a monomer to directly interact (via protein-protein interaction) with other transcription factors, repressing their ability to induce gene transcription and thus protein expression.
The search for GR ligands suitable as replacements for steroidal glucocorticoids is hindered by the fact that the other steroid hormone receptors, for example the androgen receptor (AR), the mineralocorticoid receptor (MR), and the progesterone receptor (PR), which mediate other physiological processes, have ligand binding domains homologous to GR. As a result, GR ligands have a potential for cross reactivity with these other receptors. Thus, a desired attribute of a replacement for steroidal glucocorticoids is that it binds to GR with greater affinity relative to the other steroid hormone receptors.
Recent insights have provided an opportunity for the identification of GR ligands with potent anti-inflammatory properties relative to their propensity for inducing side effects associated with glucocorticoid therapy. Glucocorticoids have long been known to repress the endogenous production of pro-inflammatory proteins such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFα).
Significantly, it has been reported that ligands selectively acting via the DNA-binding independent function of GR should suffice for the treatment of inflammatory diseases. Reichardt et al., EMBO J., 20: 7168-7173 (2001). Furthermore, many side effects of glucocorticoid therapy (e.g. hyperglycemia, diabetes mellitus, glaucoma, and muscle atrophy) are reported to be mediated by transactivational mechanisms following GR binding to DNA (see Shacke et al., Pharmacol. & Therap., 96(1): 23-43 (2002)). Thus, an agent which is capable of differentiating GR-mediated transrepression from GR-mediated transactivation is particularly desirable. Furthermore, an agent that displays limited capacity to modulate (i.e. agonize, partially agonize, partially antagonize, or antagonize) the transcriptional activity of the other steroid hormone receptors is also particularly desirable.
Thus, it is an object of the present invention to provide an agent which binds to GR with greater affinity relative to the other steroid hormone receptors. More particularly it is an object to provide an agent which binds to GR with 30-fold greater affinity relative to AR, MR, and PR. It is a further object of the present invention to provide an agent which possesses potent anti-inflammatory properties relative to its propensity for inducing side effects associated with glucocorticoid therapy. More particularly, it is an object to provide an agent which possesses potent anti-inflammatory properties relative to its propensity for inducing bone loss or osteoporosis. It is a further object of the present invention to provide an agent which displays limited capacity to modulate the activity of other steroid hormone receptors.
Tricyclic GR modulators are known in the art. For example WO 04/052847 discloses a genus of tricyclic steroid hormone receptor modulators which are useful for treating disorders susceptible to mineralocorticoid receptor or glucocorticoid receptor modulation. WO 99/33786 discloses triphenylpropanamide-derivative compounds that bind the glucocorticoid receptor and have anti-inflammatory properties.